TDP-43 is a key player in the clinical features associated with Alzheimer’s disease
- 1.6k Downloads
The aim of this study was to determine whether the TAR DNA-binding protein of 43 kDa (TDP-43) has any independent effect on the clinical and neuroimaging features typically ascribed to Alzheimer’s disease (AD) pathology, and whether TDP-43 pathology could help shed light on the phenomenon of resilient cognition in AD. Three-hundred and forty-two subjects pathologically diagnosed with AD were screened for the presence, burden and distribution of TDP-43. All had been classified as cognitively impaired or normal, prior to death. Atlas-based parcellation and voxel-based morphometry were used to assess regional atrophy on MRI. Regression models controlling for age at death, apolipoprotein ε4 and other AD-related pathologies were utilized to explore associations between TDP-43 and cognition or brain atrophy, stratified by Braak stage. In addition, we determined whether the effects of TDP-43 were mediated by hippocampal sclerosis. One-hundred and ninety-five (57 %) cases were TDP-positive. After accounting for age, apolipoprotein ε4 and other pathologies, TDP-43 had a strong effect on cognition, memory loss and medial temporal atrophy in AD. These effects were not mediated by hippocampal sclerosis. TDP-positive subjects were 10× more likely to be cognitively impaired at death compared to TDP-negative subjects. Greater cognitive impairment and medial temporal atrophy were associated with greater TDP-43 burden and more extensive TDP-43 distribution. TDP-43 is an important factor in the manifestation of the clinico-imaging features of AD. TDP-43 also appears to be able to overpower what has been termed resilient brain aging. TDP-43 therefore should be considered a potential therapeutic target for the treatment of AD.
KeywordsTDP-43 Alzheimer disease Resilience APOE ε4 Braak stage MRI
This study was funded by the US National Institute of Heath (NIA) Grants R01-AG037491 (to KAJ), R21-AG038736 (to JLW), P50-AG016574 (to RCP) and R01-AG011378 (to CRJ). We wish to thank the families of the patients who donated their brains to science allowing completion of this study. We further wish to thank Kris Johnson, Linda Rousseau, Virginia Phillips and Monica Casey-Castanedes for pathological support.
Conflict of interest
The authors declare that they have no conflicts of interest.
- 1.Agresti A, Coull BA (1998) Approximate is better than "exact" for interval estimation of binomial proportions. Am Stat 52:119–126Google Scholar
- 2.Alzheimer A (1907) Über eine eigenartige Erkrankung der Hirnrinde. Allgemeine Zeitschrift für Psychiatrie und Psychisch-Gerichtliche Medizin 64:146–148Google Scholar
- 10.Brenowitz WD, Monsell SE, Schmitt FA, Kukull WA, Nelson PT (2014) Hippocampal sclerosis of aging is a key Alzheimer’s Disease mimic: clinical-pathologic correlations and comparisons with both Alzheimer’s Disease and non-tauopathic frontotemporal lobar degeneration. J Alzheimers Dis 39:691–702. doi: 10.3233/JAD-131880 PubMedGoogle Scholar
- 14.Davidson YS, Raby S, Foulds PG et al (2011) TDP-43 pathological changes in early onset familial and sporadic Alzheimer’s disease, late onset Alzheimer’s disease and Down’s syndrome: association with age, hippocampal sclerosis and clinical phenotype. Acta Neuropathol 122:703–713. doi: 10.1007/s00401-011-0879-y CrossRefPubMedGoogle Scholar
- 27.Kaplan E, Goodglass H, Weintraub S (1983) The Boston Naming Test. Lea & Febiger, PhiladelphiaGoogle Scholar
- 29.Mattis S (1988) Dementia Rating Scale. Psychological Assessment Resources, CityGoogle Scholar
- 35.Pao WC, Dickson DW, Crook JE, Finch NA, Rademakers R, Graff-Radford NR (2011) Hippocampal sclerosis in the elderly: genetic and pathologic findings, some mimicking Alzheimer disease clinically. Alzheimer Dis Assoc Disord 25:364–368. doi: 10.1097/WAD.0b013e31820f8f50 PubMedCentralCrossRefPubMedGoogle Scholar
- 43.Uryu K, Nakashima-Yasuda H, Forman MS et al (2008) Concomitant TAR-DNA-binding protein 43 pathology is present in Alzheimer disease and corticobasal degeneration but not in other tauopathies. J Neuropathol Exp Neurol 67:555–564. doi: 10.1097/NEN.0b013e31817713b5 PubMedCentralCrossRefPubMedGoogle Scholar